Altered emotion regulation and low mood states in major depressive disorder (MDD) are thought to reflect altered corticolimbic structure and function in affected individuals, and involve the dorsolateral prefrontal cortex (DLPFC), the subgenual anterior cingulate cortex (sgACC) and the amygdala. Specifically, low GABA-related inhibition may underlie inadequate sensing and relaying of emotionally-salient stimuli by the amygdala and deficient integration of this relayed information by the sgACC with higher DLPFC processing. However, primary cellular and molecular evidence for these proposals are sparse. We have now identified a selective downregulation of somatostatin (SST), an inhibitory neuropeptide expressed in a subset of GABA neurons, in the DLPFC, sgACC and amygdala of subjects with MDD. Low SST was confirmed across cohorts, affected female subjects more robustly, and moderately correlated with the severity of the illness. At the microcircuitry level, SST GABA neurons target the distal dendrites of pyramidal neurons, but different subsets of SST neurons display different anatomical localizations and physiological properties, potentially mediating different information processing. Together, this lead us to hypothesize that low SST levels in specific cortical layers and amygdala nuclei are critical risk factors for MDD, and that additional factors determine the severity of the illness. Accordingly, we further hypothesize that, under challenging conditions, suboptimal SST function may trigger cellular and molecular maladaptive changes that lead to altered emotion regulation and low mood states, changes that will provide leads for the future development of novel therapeutics. Hence, to investigate the contribution of SST in mood regulation, we will first characterize the anatomical and microcircuitry specificity of changes in the human postmortem brains of MDD subjects (cortical layer & amygdala nuclei) (Aim 1). We will then test the low SST - risk factor hypothesis in a rodent model, and predict that mice with low SST (heterozygous mutant) will display increased vulnerability to develop high anxiety-like/depressive-like behaviors (defined as emotionality) after unpredictable chronic mild stress (Aim 2). Finally, we will use mice expressing green fluorescent protein in the SST interneuron subtype(s), which most closely corresponds to the subtype affected in MDD, to investigate low SST- and stress-associated cell-specific maladaptive molecular changes (Aim 3). In summary, low SST in MDD provide a cellular and molecular lead to investigate mechanisms of the illness, and a potential molecular link between foremost hypotheses for biological disturbances in MDD (neural network dysfunction and reduced GABA-related function). However, SST also assumes several central and peripheral functions, and pharmacological manipulation has multiple (side-)effects, so it is essential to identify maladaptive molecular changes in SST GABA neurons, as potential mediators of the phenotype and as novel and potentially selective targets for the future investigation and development of novel therapeutics aimed at relieving the burden of MDD.